PROJECT SUMMARY Over the past decade, the anesthetic agent ketamine has emerged as a promising antidepressant with both fast- onset and long-acting efficacy. However, the widespread use of ketamine for depression therapy is limited due to its sedative, hallucinogenic, amnestic, and addictive properties. The whole-brain networks that are responsible for each of ketamine?s physiologic effects remain unknown. In order to causatively assess which neural subcircuits and brain regions contribute to ketamine?s antidepressant vs other properties, there is a need for a method to noninvasively deliver ketamine locally to both cortical and deep targets within the brain. Such a method could potentially be clinically translated to provide a noninvasive therapy for modulating desired neural circuits while minimizing off-target effects. To this end, we have developed a platform of biocompatible nanoparticles that uncage a drug payload upon ultrasound application. These nanoparticles can be administered intravenously and subsequently activated within the brain?s vasculature with clinically available focused ultrasound systems. The released drug would then passively diffuse across the blood brain barrier to achieve their desired effect within the otherwise unperturbed brain. With the anesthetic propofol, we have shown that we can perform noninvasive spatiotemporally localized neuromodulation on the order of seconds and millimeters without the need for irreversible methods such as gene therapy. We further found that our nanoparticles can be used to map whole-brain responses to focal pharmacologic perturbation, highlighting their potential as a tool for neuroscientific inquiry. In this proposal, we will utilize ketamine-loaded nanoparticles to locally deliver ketamine to the infralimbic cortex (IL), a region in which local ketamine administration is known to have antidepressant-like efficacy. We will then use electrocorticography (ECOG) to quantify how ketamine action in IL entrains cortical gamma and high frequency oscillations, which are believed to drive plastic changes underlying ketamine?s antidepressant action. We will then incorporate this knowledge with behavioral studies to assess how these physiologic changes manifest behaviorally in the rat?s sensitivity to negative valence, which IL is known to modulate. We will also uncage propofol to selectively silence the IL during systemic ketamine administration with the same physiologic and behavioral endpoints. Together, this will provide unified physiologic and behavioral insight into the role of IL for ketamine?s antidepressant efficacy using behavioral paradigms that can be translated into human studies. We envision that this model could be used to identify brain targets for ketamine to induce the desired psychiatric effects while reducing unintended side effects. At the same time, our work would validate a potential clinical therapy for noninvasively delivering ketamine specifically to said targets, providing a precise pharmacologic adjunct to talk therapy or other noninvasive methods for neuromodulation in depression therapy.